Indole-3-propionic acid is an endogenic agonist of hypoxia-inducible factor-1α to protect the heart against hypoxia

Tryptophan catabolism by the gut microbiota is increasingly recognized as a hub connecting environmental challenges to cardiovascular health. By systematically profiling tryptophan metabolites in humans who had moved from low altitude to an altitude of 4300 m and in mice exposed to hypobaric hypoxia, we found that circulating and fecal levels of indole-3-propionic acid (IPA), a gut microbiota-derived tryptophan metabolite, are reduced in both settings, and these reductions correlate with the severity of cardiac injury. IPA supplementation in mice ameliorated hypobaric hypoxia-induced cardiac dysfunction. Mechanistically, IPA directly bound to hypoxia-inducible factor-1α (HIF-1α) at residue P564, competitively inhibiting its interaction with von Hippel-Lindau protein and preventing proteasomal degradation, thereby stabilizing HIF-1α. HIF-1α activation shifted cardiac metabolic substrate utilization from fatty acids to glucose and reduced oxygen consumption. Cardiomyocyte-specific HIF-1α knockout completely abolished IPA's cardioprotective effects. Moreover, gut microbiota depletion abrogated the protective effect of tryptophan against hypobaric hypoxia exposure. Finally, IPA protected against myocardial infarction in a HIF-1α-dependent manner. These results suggest that IPA is an endogenous HIF-1α agonist to protect the heart against hypoxia/ischemia, representing a promising therapeutic candidate for hypoxic/ischemic diseases.